The present invention relates to inhibitors of p38, a mammalian protein kinase involved in cell proliferation, cell death and response to extracellular stimuli. The invention also relates to methods for producing these inhibitors. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.
Protein kinases are involved in various cellular responses to extracellular signals. Recently, a family of mitogen-activated protein kinases (MAPK) has been discovered. Members of this family are Ser/Thr kinases that activate their substrates by phosphorylation [B. Stein et al., Ann. Rep. Med. Chem., 31, pp. 289-98 (1996)]. MAPKs are themselves activated by a variety of signals including growth factors, cytokines, UV radiation, and stress-inducing agents.
One particularly interesting MAPK is p38. p38, also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP) and RK, was isolated from murine pre-B cells that were transfected with the lipopolysaccharide (LPS) receptor, CD14, and induced with LPS. p38 has since been isolated and sequenced, as has the cDNA encoding it in humans and mouse. Activation of p38 has been observed in cells stimulated by stress, such as treatment of lipopolysaccharides (LPS), UV, anisomycin, or osmotic shock, and by cytokines, such as IL-1 and TNF.
Inhibition of p38 kinase leads to a blockade on the production of both IL-1 and TNF. IL-1 and TNF stimulate the production of other proinflammatory cytokines such as IL-6 and IL-8 and have been implicated in acute and chronic inflammatory diseases and in post-menopausal osteoporosis [R. B. Kimble et al., Endocrinol., 136, pp. 3054-61 (1995)].
Based upon this finding, it is believed that p38, along with other MAPKs, have a role in mediating cellular response to inflammatory stimuli, such as leukocyte accumulation, macrophage/monocyte activation, tissue resorption, fever, acute phase responses and neutrophilia. In addition, MAPKs, such as p38, have been implicated in cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and neurodegenerative disorders. Inhibitors of p38 have also been implicated in the area of pain management through inhibition of prostaglandin endoperoxide synthase-2 induction. Other diseases associated with Il-1, IL-6, IL-8 or TNF overproduction are set forth in WO 96/21654.
Others have already begun trying to develop drugs that specifically inhibit MAPKs. For example, PCT publication WO 95/31451 describes pyrazole compounds that inhibit MAPKs, and, in particular, p38.However, the efficacy of these inhibitors in vivo is still being investigated.
Accordingly, there is still a great need to develop other potent inhibitors of p38, including p38-specific inhibitors, that are useful in treating various conditions associated with p38 activation.
The present invention addresses this problem by providing compounds that demonstrate strong inhibition of p38.
These compounds have the general formula: 
wherein each of Q1 and Q2 are independently selected from a phenyl or 5-6 membered aromatic heterocyclic ring system, or a 8-10 membered bicyclic ring system comprising aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring.
A heterocyclic ring system or a heterocyclic ring contains 1 to 4 heteroatoms, which are independently selected from N, O, S, SO and SO2.
The rings that make up Q1 are substituted with 1 to 4 substituents, each of which is independently selected from halo; C1-C3 alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2 or CONRxe2x80x22; Oxe2x80x94(C1-C3)-alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2 or CONRxe2x80x22; NRxe2x80x22; OCF3; CF3; NO2; CO2Rxe2x80x2; CONRxe2x80x2; SRxe2x80x2; S(O2)N(Rxe2x80x2)2; SCF3; CN; N(Rxe2x80x2)C(O)R4; N(Rxe2x80x2)C(O)OR4; N(Rxe2x80x2)C(O)C(O)R4; N(Rxe2x80x2)S(O2)R4; N(Rxe2x80x2)R4; N(R4)2; OR4; OC(O)R4; OP(O)3H2; or Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2.
The rings that make UP Q2 are optionally substituted with up to 4 substituents, each of which is independently selected from halo; C1-C3 straight or branched alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2, S(O2)N(Rxe2x80x2)2, Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2, R3, or CONRxe2x80x22; Oxe2x80x94(C1-C3)-alkyl; Oxe2x80x94(C1-C3)-alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2, S(O2)N(Rxe2x80x2)2, Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2, R3, or CONRxe2x80x22; NRxe2x80x22; OCF3; CF3; NO2; CO2Rxe2x80x2; CONRxe2x80x2; R3; OR3; NR3; SR3; C(O)R C(O)N(Rxe2x80x2)R3; C(O)OR; SRxe2x80x2; S(O2)N(Rxe2x80x2)2; SCF3; Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2; or CN.
Q2xe2x80x2 is selected from phenyl or a 5-6 member aromatic heterocyclic ring optionally substituted with 1-3 substituents, each of which is independently selected from halogen; C1-C3 alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2, CONRxe2x80x22, or Oxe2x80x94P(O3)H2; Oxe2x80x94(C2-C3)-alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2, CONRxe2x80x22, or OP(O3)H2; OCF3; CF3; OR4; Oxe2x80x94CO2R4; Oxe2x80x94P(O3) H2; CO2Rxe2x80x2; CONRxe2x80x2; SRxe2x80x2; S(O2)N(Rxe2x80x2)2; SCF3; CN; N(Rxe2x80x2)C(O)R4; N(Rxe2x80x2)C(O)OR4; N(Rxe2x80x2)C(O)C(O)Rxe2x80x2; N(Rxe2x80x2) S(O2) R4; N(Rxe2x80x2) R4; N(R4)2; OR4; OC(O)R4; OP(O)3H2; or Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2; provided that Q2xe2x80x2 is not phenyl optionally substituted 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl.
Rxe2x80x2 is selected from hydrogen; (C1-C3)-alkyl; (C2-C3)-alkenyl or alkynyl; phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl; or a 5-6 membered heterocyclic ring system optionally substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl.
R3 is selected from 5-8 membered aromatic or non-aromatic carbocyclic or heterocyclic ring systems each optionally substituted with Rxe2x80x2, R4, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)R xe2x80x94C(O)OR4 or xe2x80x94J; or an 8-10 membered bicyclic ring system comprising aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring each optionally substituted with Rxe2x80x2, R4, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)R4, xe2x80x94C(O)OR or xe2x80x94J.
R4 is (C1-C4)-straight or branched alkyl optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, or SO2N(R2)2; or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, or SO2N(R2)2.
R5 is selected from hydrogen; (C1-C3)-alkyl optionally substituted with R3; (C2-C3)-alkenyl or alkynyl each optionally substituted with R3; phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl; or a 5-6 membered heterocyclic ring system optionally substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl.
W is selected from N(R2) SO2xe2x80x94N(R2)2; N(R2)SO2xe2x80x94N(R2)(R3); N(R2)C(O)xe2x80x94OR2; N(R2)C(O)xe2x80x94N(R2)2; N(R2)C(O)xe2x80x94N(R2)(R3); N(R2)C(O)xe2x80x94R2; N(R2)2; C(O)xe2x80x94R2; CH(OH)xe2x80x94R2; C(O)xe2x80x94N(R2)2; C(O)xe2x80x94OR2; J; or (C1-C4) straight or branched alkyl optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, R3, SO2N(R2)2, OC(O)Rxe2x80x2, OC(O)Rxe2x80x2, OC(O)N(Rxe2x80x2)2, xe2x80x94N(Rxe2x80x2)(R5), xe2x80x94C(O)N(R5)(R2), xe2x80x94C(O)Rxe2x80x2, xe2x80x94N(R2)C(O)N(R2)(R5), xe2x80x94NC(O)OR5, xe2x80x94OC(O)N(R2)(R5), or xe2x80x94J; a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, or SO2N(Rxe2x80x2)2; or a 8-10 membered carbocyclic or heterocyclic ring system optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, or SO2N(R2)2; provided that W is not an R3 substituted C1 alkyl.
Wxe2x80x2 is selected from N(R2)xe2x80x94SO2xe2x80x94Q2; N(R2)xe2x80x94CO2xe2x80x94Q2; N(R2)xe2x80x94C(O)xe2x80x94Q2; N(R2)(Q2); C(O)xe2x80x94Q2; CO2xe2x80x94Q2; C(O) N(R2)(Q2); C(Rxe2x80x2)2Q2.
Each R is independently selected from hydrogen, xe2x80x94R2, xe2x80x94N(R2)2, xe2x80x94OR2, SR2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94S (O2)xe2x80x94N(R2)2, xe2x80x94C(O)xe2x80x94OR2 or xe2x80x94C(O)R2 wherein two adjacent R are optionally bound to one another and, together with each Y to which they are respectively bound, form a 4-8 membered carbocyclic or heterocyclic ring.
R2 is selected from hydrogen, (C1-C3)-alkyl, or (C1-C3)-alkenyl; each optionally substituted with xe2x80x94N(Rxe2x80x2)2, xe2x80x94ORxe2x80x2, SRxe2x80x2, xe2x80x94C(O)xe2x80x94N(Rxe2x80x2)2, xe2x80x94S(O2)xe2x80x94N(Rxe2x80x2)2, xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94NSO2R4, xe2x80x94NSO2R3, xe2x80x94C(O)N(Rxe2x80x2)(R3), xe2x80x94NC(O)R4, xe2x80x94N(Rxe2x80x2)(R3), xe2x80x94N(Rxe2x80x2)(R4), xe2x80x94C(O)R3, xe2x80x94C(O)N(Rxe2x80x2)(R4), xe2x80x94N(R4)2, xe2x80x94C(O)Nxe2x95x90C(NH)2 or R3.
Y is N or C.
Z is CH, N, C(OCH3), C(CH3), C(NH2), C(OH) or C(F).
U is selected from R or W.
V is selected from xe2x80x94C(O)NH2, xe2x80x94P(O)(NH2)2, or xe2x80x94SO2NH2.
A, B, and C are independently selected from xe2x80x94Oxe2x80x94, xe2x80x94CHRxe2x80x2xe2x80x94, xe2x80x94CHR4xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NR4xe2x80x94 or xe2x80x94Sxe2x80x94.
J is a (C1-C4) straight chain or branched alkyl derivative substituted with 1-3 substituents selected from D, xe2x80x94Txe2x80x94C(O)Rxe2x80x2, or xe2x80x94OPO3H2.
D is selected from the group 
T is either O or NH.
G is either NH2 or OH.
In another embodiment, the invention provides pharmaceutical compositions comprising the p38 inhibitors of this invention. These compositions may be utilized in methods for treating or preventing a variety of disorders, such as cancer, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, viral diseases and neurodegenerative diseases. These compositions are also useful in methods for preventing cell death and hyperplasia and therefore may be used to treat or prevent reperfusion/ischemia in stroke, heart attacks, and organ hypoxia. The compositions are also useful in methods for preventing thrombin-induced platelet aggregation. Each of these above-described methods is also part of the present invention.
These compounds have the general formula: 
wherein each of Q1 and Q2 are independently selected from a phenyl or 5-6 membered aromatic heterocyclic ring system, or a 8-10 membered bicyclic ring system comprising aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring.
The rings that make up Q1 are substituted with 1 to 4 substituents, each of which is independently selected from halo; C1-C3 alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2 or CONRxe2x80x22; Oxe2x80x94(C1-C3)-alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2 or CONRxe2x80x22; NRxe2x80x22; OCF3; CF3; NO2; CO2Rxe2x80x2; CONRxe2x80x2; SRxe2x80x2; S(O2)N(Rxe2x80x2)2; SCF3; CN; N(Rxe2x80x2)C(O)R4; N(Rxe2x80x2)C(O)OR4; N(Rxe2x80x2)C(O)C(O)R4; N(Rxe2x80x2)S(O2)R4; N(Rxe2x80x2)R4; N(R4)2; OR4; OC(O)R4; OP(O)3H2; or Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2.
The rings that make up Q2 are optionally substituted with up to 4 substituents, each of which is independently selected from halo; C1-C3 straight or branched alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2, S(O2)N(Rxe2x80x2)2, Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2, R3, or CONRxe2x80x22; Oxe2x80x94(C1-C3)-alkyl; Oxe2x80x94(C1-C3)-alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2, S(O2)N(Rxe2x80x2)2, Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2, R3, or CONRxe2x80x22; NRxe2x80x22; OCF3; CF3; NO2; CO2Rxe2x80x2; CONRxe2x80x2; R3; OR3; NR3; SR3; C(O)R3; C(O)N(Rxe2x80x2)R3; C(O)OR3; SRxe2x80x2; S(O2)N(Rxe2x80x2)2; SCF3; Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2; or CN.
Q2xe2x80x2 is selected from phenyl or a 5-6 member aromatic heterocyclic ring optionally substituted with 1-3 substituents, each of which is independently selected from halogen; C1-C3 alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2, CONRxe2x80x22, or Oxe2x80x94P(O3) H2; Oxe2x80x94(C2-C3)-alkyl optionally substituted with NRxe2x80x22, ORxe2x80x2, CO2Rxe2x80x2, CONRxe2x80x22, or OP (O3) H2; OCF3; CF3; OR4; Oxe2x80x94CO2R4; Oxe2x80x94P (O3) H2; CO2Rxe2x80x2; CONRxe2x80x2 SRxe2x80x2; S(O2)N(Rxe2x80x2)2; SCF3; CN; N(Rxe2x80x2)C(o)R4; N(Rxe2x80x2)C(O)OR4; N(Rxe2x80x2)C(O)C(O)R4; N(Rxe2x80x2)S(O2)R4; N(Rxe2x80x2)R4; N(R4)2; ORxe2x80x2; OC(O)R4; OP(O)3H2; or Nxe2x95x90Cxe2x80x94N(Rxe2x80x2)2; provided that Q2xe2x80x2 is not phenyl optionally substituted 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl.
Rxe2x80x2 is selected from hydrogen; (C1-C3)-alkyl; (C2-C3)-alkenyl or alkynyl; phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl; or a 5-6 membered heterocyclic ring system optionally substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl.
R3 is selected from 5-8 membered aromatic or non-aromatic carbocyclic or heterocyclic ring systems each optionally substituted with Rxe2x80x2, R4, C(O)Rxe2x80x2, xe2x80x94C(O)R4, xe2x80x94C(O)OR4 or xe2x80x94J; or an 8-10 membered bicyclic ring system comprising aromatic carbocyclic rings, aromatic heterocyclic rings or a combination of an aromatic carbocyclic ring and an aromatic heterocyclic ring each optionally substituted with Rxe2x80x2, R4, xe2x80x94C(O)Rxe2x80x2, xe2x80x94C(O)R4, xe2x80x94C(O)OR4 or xe2x80x94J.
R4 is (C1-C4)-straight or branched alkyl optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, or SO2N(R2)2; or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, or SO2N(R2)2.
R is selected from hydrogen; (C1-C3)-alkyl optionally substituted with R3; (C2-C3)-alkenyl or alkynyl each optionally substituted with R3; phenyl or phenyl substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl; or a 5-6 membered heterocyclic ring system optionally substituted with 1 to 3 substituents independently selected from halo, methoxy, cyano, nitro, amino, hydroxy, methyl or ethyl.
W is selected from N(R2) SO2xe2x80x94N(R2)2; N(R2) SO2xe2x80x94N(R2)(R3); N(R2)C(O)xe2x80x94OR2; N(R2)C(O)xe2x80x94N(R2)2; N(R2)C(O)xe2x80x94N(R2)(R3); N(R2)C(O)xe2x80x94R2; N(R2)2; C(O)xe2x80x94R2; CH(OH)xe2x80x94R2; C(O)xe2x80x94N(R2)2; C(O)xe2x80x94OR2; J; or (C1-C4) straight or branched alkyl optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, R3, SO2N(R2)2, OC(O)R2, OC(O)Rxe2x80x2, OC(O)N(R2)2, xe2x80x94N(R4)(R5), xe2x80x94C(O)N(R5)(R2), xe2x80x94C(O)R5, xe2x80x94N(R2)C(O)N(R2)(R5), xe2x80x94NC(O)OR5, xe2x80x94OC(O)N(R2)(R5), or xe2x80x94J; a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, or SO2N(R2)2; or a 8-10 membered carbocyclic or heterocyclic ring system optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, or SO2N(R2)2; provided that W is not an R substituted C1 alkyl.
Wxe2x80x2 is selected from N(R2)xe2x80x94SO2xe2x80x94Q2; N(R2)xe2x80x94CO2xe2x80x94Q2; N(R2)xe2x80x94C(O)xe2x80x94Q2; N(R2)(Q2); C(O)xe2x80x94Q2; CO2xe2x80x94Q2; C(O)N(R2)(Q2); C(R2)2Q2.
Each R is independently selected from hydrogen, xe2x80x94R2, xe2x80x94N(R2)2, xe2x80x94OR2, SR2, xe2x80x94C(O)xe2x80x94N(R2)2, xe2x80x94S(O2)xe2x80x94N(R2)2, xe2x80x94C(O)xe2x80x94OR2 or xe2x80x94C(O)R2 wherein two adjacent R are optionally bound to one another and, together with each Y to which they are respectively bound, form a 4-8 membered carbocyclic or heterocyclic ring.
When the two R components form a ring together with the Y components to which they are respectively bound, it will obvious to those skilled in the art that a terminal hydrogen from each unfused R component will be lost. For example, if a ring structure is formed by binding those two R components together, one being xe2x80x94NHxe2x80x94CH3 and the other being xe2x80x94CH2xe2x80x94CH3, one terminal hydrogen on each R component (indicated in bold) will be lost. Therefore, the resulting portion of the ring structure will have the formula xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94.
R2 is selected from hydrogen, (C1-C3)-alkyl, or (C1-C3)-alkenyl; each optionally substituted with xe2x80x94N(Rxe2x80x2)2, xe2x80x94ORxe2x80x2, SRxe2x80x2, xe2x80x94C(O)xe2x80x94N(Rxe2x80x2)2, xe2x80x94S (O2)xe2x80x94N(Rxe2x80x2)2, xe2x80x94C(O)xe2x80x94ORxe2x80x2, xe2x80x94NSO2R4, xe2x80x94NSO2R3, xe2x80x94C(O)N(Rxe2x80x2)(R3), xe2x80x94NC(O)R4, xe2x80x94N(Rxe2x80x2)(R3), xe2x80x94N(Rxe2x80x2)(R4), xe2x80x94C(O)R3, xe2x80x94C(O)N(Rxe2x80x2)(R4), xe2x80x94N(R4)2, xe2x80x94C(O)Nxe2x95x90C(NH)2 or R3.
Y is N or C.
Z is CH, N, C(OCH3), C(CH3), C(NH2), C(OH) or C(F)
U is selected from R or W.
V is selected from xe2x80x94C(O)NH2, xe2x80x94P(O)(NH2)2, or xe2x80x94SO2NH2.
A, B, and C are independently selected from xe2x80x94Oxe2x80x94, xe2x80x94CHRxe2x80x2xe2x80x94, xe2x80x94CHR4xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NR4xe2x80x94 or xe2x80x94Sxe2x80x94.
J is a (C1-C4) straight chain or branched alkyl derivative substituted with 1-3 substituents selected from D, xe2x80x94Txe2x80x94C(O)Rxe2x80x2, or xe2x80x94OPO3H2.
D is selected from the group 
T is either O or NH.
G is either NH2 or OH.
According to a preferred embodiment, Q1 is selected from phenyl or pyridyl containing 1 to 3 substituents, wherein at least one of said substituents is in the ortho position and said substituents are independently selected from chloro, fluoro, bromo, xe2x80x94CH3, xe2x80x94OCH3, xe2x80x94OH, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94O(CH2)2CH3, NH2, 3,4-methylenedioxy, xe2x80x94N(CH3)2, xe2x80x94NHxe2x80x94S(O)2-phenyl, xe2x80x94NHxe2x80x94C(O)Oxe2x80x94CH2-4-pyridine, xe2x80x94NHxe2x80x94C(O)CH2-morpholine, xe2x80x94NHxe2x80x94C(O)CH2xe2x80x94N(CH3)2, xe2x80x94NHxe2x80x94C(O)CH2-piperazine, xe2x80x94NHxe2x80x94C(O)CH2-pyrrolidine, xe2x80x94NHxe2x80x94C(O)C(O)-morpholine, xe2x80x94NHxe2x80x94C(O)C(O)-piperazine, xe2x80x94NHxe2x80x94C(O)C(O)-pyrrolidine, xe2x80x94Oxe2x80x94C(O)CH2xe2x80x94N(CH3)2, or xe2x80x94Oxe2x80x94(CH2)2xe2x80x94N(CH3)2.
Even more preferred are phenyl or pyridyl containing at least 2 of the above-indicated substituents both being in the ortho position.
Some specific examples of preferred Q1 are: 
Most preferably, Q1 is selected from 2-fluoro-6-trifluoromethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-chloro-4-hydroxyphenyl, 2-chloro-4-aminophenyl, 2,6-dichloro-4-aminophenyl, 2,6-dichloro-3-aminophenyl, 2,6-dimethyl-4-hydroxyphenyl, 2-methoxy-3,5-dichloro-4-pyridyl, 2-chloro-4,5 methylenedioxy phenyl, or 2-chloro-4-(N-2-morpholino-acetamido)phenyl.
According to a preferred embodiment, Q2 is phenyl, pyridyl or naphthyl containing 0 to 3 substituents, wherein each substituent is independently selected from chloro, fluoro, bromo, methyl, ethyl, isopropyl, xe2x80x94OCH3, xe2x80x94OH, xe2x80x94NH2, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94SCH3, xe2x80x94OCH3, xe2x80x94C(O)OH, xe2x80x94C(O)OCH3, xe2x80x94CH2NH2, xe2x80x94N(CH3)2, xe2x80x94CH2-pyrrolidine and xe2x80x94CH2OH.
Some specific examples of preferred Q2 are: 
unsubstituted 2-pyridyl or unsubstituted phenyl.
Most preferred are compounds wherein Q2 is selected from phenyl, 2-isopropylphenyl, 3,4-dimethylphenyl, 2-ethylphenyl, 3-fluorophenyl, 2-methylphenyl, 3-chloro-4-fluorophenyl, 3-chlorophenyl, 2-carbomethoxylphenyl, 2-carboxyphenyl, 2-methyl-4-chlorophenyl, 2-bromophenyl, 2-pyridyl, 2-methylenehydroxyphenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, 2-chloro-4-fluorphenyl, 2,4-difluorophenyl, 2-hydroxy-4-fluorphenyl, 2-methylenehydroxy-4-fluorophenyl, 1-naphthyl, 3-chloro-2-methylenehydroxy, 3-chloro-2-methyl, or 4-fluoro-2-methyl.
According to another preferred embodiment, each Y is C.
According an even more preferred embodiment, each Y is C and the R and U attached to each Y component is selected from hydrogen or methyl.
According to another preferred embodiment, W is a 0-4 atom chain terminating in an alcohol, amine, carboxylic acid, ester, amide, or heterocycle.
Some specific examples of preferred W are: 
Most preferably, W is selected from: 
U has the same preferred and most preferred embodiments as W.
According to an even more preferred embodiment, each Y is C, and W and/or U is not hydrogen.
Some preferred embodiments are provided in Table 1 to 6 below:
Particularly preferred embodiments include: 
Particularly preferred embodiments also include: 
wherein X is NH2 or N(CH3)2; 
wherein X is OH, NH2, or N(CH3)2.
Other particularly preferred embodiments include: 
Other particularly preferred embodiments include: 
Other particularly preferred embodiments 
Most preferred embodiments include: 
According to another embodiment, the present invention provides methods of producing the above-identified inhibitors of p38 of the formulae (Ia),(Ib), (Ic), (Id) and (Ie). Representative synthesis schemes for formula (Ia) are depicted below.
Schemes 1-3 illustrate the preparation of compounds in which W is either an amino, carboxyl or an aldehyde function. In each case the particular moiety may be modified through chemistry well known in the literature. For example the final amino compounds D and N (schemes 1 and 4 respectively) may be acylated, sulfonylated or alkylated to prepare compounds within the scope of W. In all schemes, the L1 and L2 groups on the initial materials are meant to represent leaving groups ortho to the nitrogen atom in a heterocyclic ring. For example, compound A may be 2,6-dichloro-3 nitro pyridine. 
In Scheme 1, W is selected from amino-derivatized compounds such as N(R2) SO2xe2x80x94N(R2)2; N(R2)SO2xe2x80x94N(R2)(R3); N(R2)C(O)xe2x80x94N(R2)2; N N(R2)(R3); N(R2)C(O)xe2x80x94R2; or N(R2)2.
In Scheme 1, the Q2 ring is introduced utilizing one of many reactions know in the art which result in the production of biaryl compounds. One example may be the reaction of an aryl lithium compound with the pyridine intermediate A. Alternatively, an arylmetalic compound such as an aryl stannane or an aryl boronic acid may be reacted with the aryl halide portion (intermediate A) in the presence of a Pdxc2x0 catalyst to form product B. In the next step, a Q1 substituted derivative such as a phenyl acetonitrile derivative may be treated with a base such as sodium hydride, sodium amide, LDA, lithium hexamethyldisilazide or any number of other non-nucleophilic bases to deprotonate the position alpha to the cyano group, which represents a masked amide moiety. This anion is then contacted with intermediate B to form C. The nitrile or equivalent group of intermediate C is then hydrolyzed to form the amide and the nitro group is subjected to reducing conditions to form the amine intermediate D. Intermediate D is then used to introduce various functionality defined by W through chemistry such as acylation, sulfonylation or alkylation reactions well known in the literature. Depending on the regiochemistry of the first two steps of this procedure, the first two steps may need to be reversed. 
In Scheme 2, W is selected from carboxyl-derivatized compounds such as C(O)xe2x80x94R2; CH(OH)xe2x80x94R2; C(O)xe2x80x94N(R2)2; or C(O)xe2x80x94OR2.
Scheme 2 generally follows the procedures described for Scheme 1 except that a carboxyl intermediate such as E is the starting material. The first two steps mirror Scheme 1, and, as mentioned for Scheme 1, may be reversed depending on the regiochemistry of specific examples. Intermediate G is formed from these first two steps and this material may be hydrolyzed as mention to for the carboxyl intermediate H. The carboxyl group may then be modified according to well-known procedures from the literature to prepare analogs with defined W substituents such as acylations, amidations and esterifications. 
In Scheme 3, W is selected from (C1-C4) straight or branched alkyl optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, R3, or SO2N(R2)2; or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, or SO2N(R2)2; provided that W is not an R3 substituted C1 alkyl.
In scheme 3 a pyridine derivative is metalated and quenched with one of many known electrophiles which can generate an aldehyde, to form intermediate I. The aldehyde can then be masked to form the dimethyl acetal J. This intermediate is then carried on as described in scheme 1 and 2 to introduce the Q1 and Q2 substituents, to produce intermediate L. As before, these two steps may be interchanged depending on specific regiochemistry. The masked aldehyde of L may then be deprotected and utilized to form compounds with the defined W substitution using well know chemistry such as alkylations and reductive aminations.
Schemes 4-6 are similar to schemes 1-3 with the exception that the targeted compounds are those in which Z=Nitrogen. The steps for these schemes parallel 1-3 with the exception that the alkylation utilizing a phenyl acetonitrile is replaced with a reaction with a Q1 amine derivative such as a substituted aniline derivative. The amide portion of the molecule is then introduced in an acylation reaction with, for example, chlorosulfonyl isocyanate. 
In Scheme 4, W is selected from amino-derivatized groups such as N(R2)SO2xe2x80x94N(R2)2; N(R2)SO2xe2x80x94N(R2)(R3); N(R2)C(O)xe2x80x94OR2; N(R2)C(O)xe2x80x94N(R2)2; N(R2)C(O)xe2x80x94N(R2)(R3); N(R2)C(O)xe2x80x94R2; or N(R2)2.
In Scheme 4, intermediate B (from scheme 1) is treated with, for example, an aniline derivative in the presence of a base such as potassium carbonate. Additionally, a palladium catalyst may be utilized to enhance the reactivity of this general type of reaction, if needed. The resulting amine derivative is then acylated to form intermediate M. The nitro group of M is then reduced to form N and the amino group may then be derivatized as described for scheme 1. As mentioned for schemes 1-3, the steps involved in the introduction of the Q1 and Q2 substituents may be interchanged depending on the specific regiochemistry of specific compounds. 
In Scheme 5, W is selected from carboxyl-derivatized groups such as C(O)xe2x80x94R2; CH(OH)xe2x80x94R2; C(O)xe2x80x94N(R2)2; or C(O)xe2x80x94OR2. 
In Scheme 6, W is selected from (C1-C4) straight or branched alkyl optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, R3, or SO2N(R2)2; or a 5-6 membered carbocyclic or heterocyclic ring system optionally substituted with N(Rxe2x80x2)2, ORxe2x80x2, CO2Rxe2x80x2, CON(Rxe2x80x2)2, or SO2N(R2)2; provided that W is not an R3 substituted C1 alkyl.
Schemes 5 and 6 generally follow the procedures mentioned above.
One having skill in the art will recognize schemes 1-6 may be used to synthesize compounds having the general formula of (Ib), (Ic), (Id) and (Ie).
According to another embodiment of the invention, the activity of the p38 inhibitors of this invention may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of activated p38. Alternate in vitro assays quantitate the ability of the inhibitor to bind to p38 and may be measured either by radiolabelling the inhibitor prior to binding, isolating the inhibitor/p38 complex and determining the amount of radiolabel bound, or by running a competition experiment where new inhibitors are incubated with p38 bound to known radioligands.
Cell culture assays of the inhibitory effect of the compounds of this invention may determine the amounts of TNF, IL-1, IL-6 or IL-8 produced in whole blood or cell fractions thereof in cells treated with inhibitor as compared to cells treated with negative controls. Level of these cytokines may be determined through the use of commercially available ELISAs.
An in vivo assay useful for determining the inhibitory activity of the p38 inhibitors of this invention are the suppression of hind paw edema in rats with Mycobacterium butyricum-induced adjuvant arthritis. This is described in J. C. Boehm et al., J. Med. Chem., 39, pp. 3929-37 (1996), the disclosure of which is herein incorporated by reference. The p38 inhibitors of this invention may also be assayed in animal models of arthritis, bone resorption, endotoxin shock and immune function, as described in A. M. Badger et al., J. Pharmacol. Experimental Therapeutics, 279, pp. 1453-61 (1996), the disclosure of which is herein incorporated by reference.
The p38 inhibitors or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which comprise an amount of p38 inhibitor effective to treat or prevent a p38-mediated condition and a pharmaceutically acceptable carrier, are another embodiment of the present invention.
The term xe2x80x9cp38-mediated conditionxe2x80x9d, as used herein means any disease or other deleterious condition in which p38 is known to play a role. This includes conditions known to be caused by IL-1, TNF, IL-6 or IL-8 overproduction. Such conditions include, without limitation, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, neurodegenerative diseases, allergies, reperfusion/ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, thrombin-induced platelet aggregation, and conditions associated with prostaglandin endoperoxidase synthase-2.
Inflammatory diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, acute pancreatitis, chronic pancreatitis, asthma, allergies, and adult respiratory distress syndrome.
Autoimmune diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves"" disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn""s disease, psoriasis, or graft vs. host disease.
Destructive bone disorders which may be treated or prevented by the compounds of this invention include, but are not limited to, osteoporosis, osteoarthritis and multiple myeloma-related bone disorder.
Proliferative diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi""s sarcoma, and multiple myeloma.
Angiogenic disorders which may be treated or prevented by the compounds of this invention include solid tumors, ocular neovasculization, infantile haemangiomas.
Infectious diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, sepsis, septic shock, and Shigellosis.
Viral diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis.
Neurodegenerative diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, Alzheimer""s disease, Parkinson""s disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury.
xe2x80x9cp38-mediated conditionsxe2x80x9d also include ischemia/reperfusion in stroke, heart attacks, myocardial ischemia, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, and thrombin-induced platelet aggregation.
In addition, p38 inhibitors of the instant invention are also capable of inhibiting the expression of inducible pro-inflammatory proteins such as prostaglandin endoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2 (COX-2). Therefore, other xe2x80x9cp38-mediated conditionsxe2x80x9d which may be treated by the compounds of this invention include edema, analgesia, fever and pain, such as neuromuscular pain, headache, cancer pain, dental pain and arthritis pain.
The diseases that may be treated or prevented by the p38 inhibitors of this invention may also be conveniently grouped by the cytokine (IL-1, TNF, IL-6, IL-8) that is believed to be responsible for the disease.
Thus, an IL-1-mediated disease or condition includes rheumatoid arthritis, osteoarthritis, stroke, endotoxemia and/or toxic shock syndrome, inflammatory reaction induced by endotoxin, inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter""s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, diabetes, pancreatic xcex2-cell disease and Alzheimer""s disease.
TNF-mediated disease or condition includes, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, AIDS, ARC or malignancy, keloid formation, scar tissue formation, Crohn""s disease, ulcerative colitis or pyresis. TNF-mediated diseases also include viral infections, such as HIV, CMV, influenza and herpes; and veterinary viral infections, such as lentivirus infections, including, but not limited to equine infectious anemia virus, caprine arthritis virus, visna virus or maedi virus; or retrovirus infections, including feline immunodeficiency virus, bovine immunodeficiency virus, or canine immunodeficiency virus.
IL-8 mediated disease or condition includes diseases characterized by massive neutrophil infiltration, such as psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis.
In addition, the compounds of this invention may be used topically to treat or prevent conditions caused or exacerbated by IL-1 or TNF. Such conditions include inflamed joints, eczema, psoriasis, inflammatory skin conditions such as sunburn, inflammatory eye conditions such as conjunctivitis, pyresis, pain and other conditions associated with inflammation.
In addition to the compounds of this invention, pharmaceutically acceptable salts of the compounds of this invention may also be employed in compositions to treat or prevent the above-identified disorders.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and Nxe2x80x94(C1-4 alkyl)4+ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term xe2x80x9cparenteralxe2x80x9d as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.
Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
The amount of p38 inhibitor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of inhibitor will also depend upon the particular compound in the composition.
According to another embodiment, the invention provides methods for treating or preventing a p38-mediated condition comprising the step of administering to a patient one of the above-described pharmaceutical compositions. The term xe2x80x9cpatientxe2x80x9d, as used herein, means an animal, preferably a human.
Preferably, that method is used to treat or prevent a condition selected from inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, degenerative diseases, allergies, reperfusion/ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, and thrombin-induced platelet aggregation.
According to another embodiment, the inhibitors of this invention are used to treat or prevent an IL-1, IL-6, IL-8 or TNF-mediated disease or condition. Such conditions are described above.
Depending upon the particular p38-mediated condition to be treated or prevented, additional drugs, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention. For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the p38 inhibitors of this invention to treat proliferative diseases.
Those additional agents may be administered separately, as part of a multiple dosage regimen, from the p38 inhibitor-containing composition. Alternatively, those agents may be part of a single dosage form, mixed together with the p38 inhibitor in a single composition.
In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.